Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus.

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer's disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory in rats.

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of biconditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-s trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

"Thalamic aphasia" after stroke is associated with left anterior lesion location.

BACKGROUND: Aphasic symptoms are typically associated with lesions of the left fronto-temporal cortex. Interestingly, aphasic symptoms have also been described in patients with thalamic strokes in anterior, paramedian or posterolateral location. So far, systematic analyses are missing. METHODS: We conducted a retrospective analysis of consecutive patients admitted to our tertiary stroke care center between January 2016 and July 2017 with image-based (MRI) proven ischemic stroke. We evaluated stroke lesion location, using 3-T MRI, and presence of aphasic symptoms. RESULTS: Out of 1064 patients, 104 (9.8%) presented with a thalamic stroke, 52 of which (4.9%) had an isolated lesion in the thalamus (ILT). In patients with ILT, 6/52 had aphasic symptoms. Aphasic symptoms after ILT were only present in patients with left anterior lesion location (n = 6, 100% left anterior vs. 0% other thalamic location, p < 0.001). CONCLUSIONS: Aphasic symptoms in thalamic stroke are strongly associated with left anterior lesion location. In thalamo-cortical language networks, specifically the nuclei in the left anterior thalamus could play an important role in integration of left cortical information with disconnection leading to aphasic symptoms.

Do the rat anterior thalamic nuclei contribute to behavioural flexibility?

The rodent anterior thalamic nuclei (ATN) are vital for spatial memory. A consideration of their extensive frontal connections suggests that these nuclei may also subserve non-spatial functions. The current experiments explored the importance of the ATN for different aspects of behavioural flexibility, including their contribution to tasks typically associated with frontal cortex. In Experiment 1, rats with ATN lesions were tested on a series of response and visual discriminations in an operant box and, subsequently, in a water tank. The tasks included assessments of reversal learning as well switches between each discrimination dimension. Results revealed a mild and transient deficit on the operant task that was not specific to any stage of the procedure. In the water tank, the lesion animals were impaired on the reversal of a spatial discrimination but did not differ from controls on any other measure. Experiment 2 examined the impact of ATN damage on a rodent analogue of the 'Stroop', which assesses response choice during stimulus conflict. The lesion animals successfully acquired this task and were able to use contextual information to disambiguate conflicting cue information. However, responding during the initial presentation of conflicting cue information was affected by the lesion. Taken together, these results suggest that the ATN are not required for aspects of behavioural flexibility (discrimination learning, reversals or high-order switches) typically associated with the rat medial prefrontal cortex. The results from Experiment 2 suggest that the non-spatial functions of the ATN may be more aligned with those of the anterior cingulate cortex.

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down syndrome.

The anterior thalamic nuclei are important for spatial and episodic memory, however, surprisingly little is known about the status of these nuclei in neurological conditions that present with memory impairments, such as Down syndrome. We quantified neurons and glial cells in the anterior thalamic nuclei of four older patients with Down syndrome. There was a striking reduction in the volume of the anterior thalamic nuclei and this appeared to reflect the loss of approximately 70% of neurons. The number of glial cells was also reduced but to a lesser degree than neurons. The anterior thalamic nuclei appear to be particularly sensitive to effects of aging in Down syndrome and the pathology in this region likely contributes to the memory impairments observed. These findings reaffirm the importance of examining the status of the anterior thalamic nuclei in conditions where memory impairments have been principally assigned to pathology in the medial temporal lobe.

Thalamic shape and volume abnormalities in female patients with panic disorder.

The thalamus is believed to play crucial role in processing viscero-sensory information, and regulating the activity of amygdala in patients with panic disorder (PD). Previous functional neuroimaging studies have detected abnormal activation in the thalamus in patients with PD compared with healthy control subjects (HC). Very few studies, however, have investigated for volumetric abnormalities in the thalamus in patients with PD. Furthermore, to the best of our knowledge, no previous study has investigated for shape abnormalities in the thalamus in patients with PD. Twenty-five patients with PD and 25 HC participants (all female) were recruited for the study. A voxel-wise volume comparison analysis and a vertex-wise shape analysis were conducted to evaluate structural abnormalities in the PD patients compared to HC. The patients with PD demonstrated significant gray matter volume reductions in the thalamus bilaterally, relative to the HC. The shape analysis detected significant inward deformation in some thalamic regions in the PD patients, including the anterior nucleus, mediodorsal nucleus, and pulvinar nucleus. PD patients showed shape deformations in key thalamic regions that are believed to play a role in regulating emotional and cognitive functions.

Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice.

Nowadays, amyotrophic lateral sclerosis (ALS) is considered as a multisystem disorder, characterized by a primary degeneration of motor neurons as well as neuropathological changes in non-motor regions. Neurodegeneration in subcortical areas, such as the thalamus, are believed to contribute to cognitive and behavioral abnormalities in ALS patients. In the present study, we investigated neurodegenerative changes including neuronal loss and glia pathology in the anterodorsal thalamic nucleus (AD) of SOD1(G93A) mice, a widely used animal model for ALS. We detected massive dendrite swelling and neuronal loss in SOD1(G93A) animals, which was accompanied by a mild gliosis. Furthermore, misfolded SOD1 protein and autophagy markers were accumulating in the AD. Since innate immunity and activation inflammasomes seem to play a crucial role in ALS, we examined protein expression of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) and the cytokine interleukin 1 beta (IL1ß) in AD glial cells and neurons. NLRP3 and ASC were significantly up-regulated in the AD of SOD1(G93A) mice. Finally, co-localization studies revealed expression of NLRP3, ASC and IL1ß in neurons. Our study yielded two main findings: (i) neurodegenerative changes already occur at an early symptomatic stage in the AD and (ii) increased inflammasome expression may contribute to neuronal cell death. In conclusion, neurodegeneration in the anterior thalamus may critically account for cognitive changes in ALS pathology.

Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood-brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid-induced epileptic rats.

Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood-brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti-inflammatory effect in epileptic models.

Medial thalamic stroke and its impact on familiarity and recollection.

Models of recognition memory have postulated that the mammillo-thalamic tract (MTT)/anterior thalamic nucleus (AN) complex would be critical for recollection while the Mediodorsal nucleus (MD) of the thalamus would support familiarity and indirectly also be involved in recollection (Aggleton et al., 2011). 12 patients with left thalamic stroke underwent a neuropsychological assessment, three verbal recognition memory tasks assessing familiarity and recollection each using different procedures and a high-resolution structural MRI. Patients showed poor recollection on all three tasks. In contrast, familiarity was spared in each task. No patient had significant AN lesions. Critically, a subset of 5 patients had lesions of the MD without lesions of the MTT. They also showed impaired recollection but preserved familiarity. Recollection is therefore impaired following MD damage, but familiarity is not. This suggests that models of familiarity, which assign a critical role to the MD, should be reappraised.

Deep brain stimulation of the anterior nucleus of the thalamus reverses the gene expression of cytokines and their receptors as well as neuronal degeneration in epileptic rats.

BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is effective in seizure control. However, the mechanisms remain unclear. METHODS: Sixty-four rats were randomly assigned to the control group, the kainic acid (KA) group, the sham-DBS group and the DBS group. Video-electroencephalogram (EEG) was used to monitor seizures. Quantitative real time PCR (qPCR) was applied for detecting interleukin-1 beta (IL-1ß), IL-1 receptor (IL-1R), IL-6, IL-6 receptor (IL-6R), gp130, tumor necrosis factor-alpha (TNF-α), TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2) expression 12h after the establishment of an epileptic model. The neuronal structural degeneration in the hippocampus was evaluated with transmission electron microscopy (TEM) at this same time point. RESULTS: The seizure frequency was 48.6% lower in the DBS group compared with the sham-DBS group (P<0.01). The expression of IL-1ß, IL-1R, IL-6, IL-6R, gp130, TNF-α and TNF-R1 was elevated in both the KA and the sham group compared with the control group (all Ps<0.01). Additionally, ANT-DBS was able to reverse this gene expression pattern in the DBS group compared with the sham-DBS group (all Ps<0.01). There was no significant difference in TNF-R2 expression among the four groups. The neuronal structural degeneration in the KA group and the sham-DBS group was more severe than that in the control group (injury scores, all Ps<0.01). ANT-DBS was also capable of relieving the degeneration compared with the sham-DBS group (injury score, P<0.01). CONCLUSIONS: This study demonstrated that ANT-DBS can reduce seizure frequency in the early stage in epileptic rats as well as relieve the pro-inflammatory state and neuronal injury, which may be one of the most effective mechanisms of ANT-DBS against epileptogenesis.

Impact of Strategically Located White Matter Hyperintensities on Cognition in Memory Clinic Patients with Small Vessel Disease.

BACKGROUND AND PURPOSE: Studies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to be functionally important. We examined the relation between WMH location and cognition in a memory clinic cohort of patients with sporadic SVD. METHODS: A total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory. RESULTS: Region of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, independent of total WMH volume. An independent assumption-free voxel-wise analysis identified strategic voxels in these same tracts. Region of interest-based analyses showed that WMH volume within the anterior thalamic radiation explained 6.8% of variance in executive functioning, compared to 3.9% for total WMH volume; WMH volume within the forceps minor explained 4.6% of variance in visuomotor speed and 4.2% of variance in memory, compared to 1.8% and 1.3% respectively for total WMH volume. CONCLUSIONS: Our findings identify the anterior thalamic radiation and forceps minor as strategic white matter tracts in which WMHs are most strongly associated with cognitive impairment in memory clinic patients with SVD. WMH volumes in individual tracts explained more variance in cognition than total WMH burden, emphasizing the importance of lesion location when addressing the functional consequences of WMHs.

Do the anterior and lateral thalamic nuclei make distinct contributions to spatial representation and memory?

The anterior and lateral thalamus has long been considered to play an important role in spatial and mnemonic cognitive functions; however, it remains unclear whether each region makes a unique contribution to spatial information processing. We begin by reviewing evidence from anatomical studies and electrophysiological recordings which suggest that at least one of the functions of the anterior thalamus is to guide spatial orientation in relation to a global or distal spatial framework, while the lateral thalamus serves to guide behavior in relation to a local or proximal framework. We conclude by reviewing experimental work using targeted manipulations (lesion or neuronal silencing) of thalamic nuclei during spatial behavior and single-unit recordings from neuronal representations of space. Our summary of this literature suggests that although the evidence strongly supports a working model of spatial information processing involving the anterior thalamus, research regarding the role of the lateral thalamus is limited and requires further attention. We therefore identify a number of major gaps in this research and suggest avenues of future study that could potentially solidify our understanding of the relative roles of anterior and lateral thalamic regions in spatial representation and memory.

Anterior thalamic nuclei lesions and recovery of function: Relevance to cognitive thalamus.

Injury to the anterior thalamic nuclei (ATN) and their neural connections is the most consistent neuropathology associated with diencephalic amnesia. ATN lesions in rats produce memory impairments that support a key role for this region within an extended hippocampal system of complex overlapping neural connections. Environmental enrichment is a therapeutic tool that produces substantial, although incomplete, recovery of memory function after ATN lesions, even after the lesion-induced deficit has become established. Similarly, the neurotrophic agent cerebrolysin, also counters the negative effects of ATN lesions. ATN lesions substantially reduce c-Fos expression and spine density in the retrosplenial cortex, and reduce spine density on CA1 neurons; only the latter is reversed by enrichment. We discuss the implications of this evidence for the cognitive thalamus, with a proposal that there are genuine interactions among different but allied thalamo-cortical systems that go beyond a simple summation of their separate effects.

Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits?

Lesions of the rodent anterior thalamic nuclei cause severe deficits to multiple spatial learning tasks. Possible explanations for these effects are examined, with particular reference to T-maze alternation. Anterior thalamic lesions not only impair allocentric place learning but also disrupt other spatial processes, including direction learning, path integration, and relative length discriminations, as well as aspects of nonspatial learning, e.g., temporal discriminations. Working memory tasks, such as T-maze alternation, appear particularly sensitive as they combine an array of these spatial and nonspatial demands. This sensitivity partly reflects the different functions supported by individual anterior thalamic nuclei, though it is argued that anterior thalamic lesion effects also arise from covert pathology in sites distal to the thalamus, most critically in the retrosplenial cortex and hippocampus. This two-level account, involving both local and distal lesion effects, explains the range and severity of the spatial deficits following anterior thalamic lesions. These findings highlight how the anterior thalamic nuclei form a key component in a series of interdependent systems that support multiple spatial functions.

Complex motor-cognitive factors processed in the anterior nucleus of the thalamus: an intracerebral recording study.

Cognitive adverse effects were reported after the deep brain stimulation (DBS) of the anterior nucleus of the thalamus (AN) in epilepsy. As the AN may have an influence on widespread neocortical networks, we hypothesized that the AN, in addition to its participation in memory processing, may also participate in cognitive activities linked with the frontal neocortical structures. The aim of this study was to investigate whether the AN might participate in complex motor-cognitive activities. Three pharmacoresistant epilepsy patients implanted with AN-DBS electrodes performed two tasks involving the writing of single letters: (1) copying letters from a monitor; and (2) writing of any letter other than that appearing on the monitor. The cognitive load of the second task was increased. The task-related oscillatory changes and evoked potentials were assessed. Local event-related alpha and beta desynchronization were more expressed during the second task while the lower gamma synchronization decreased. The local field event-related potentials were elicited by the two tasks without any specific differences. The AN participates in cognitive networks processing complex motor-cognitive tasks. Attention should be paid to executive functions in subjects undergoing AN-DBS.

Contralateral hyperhidrosis in anterior thalamic infarction.

A 62-year-old male complained of contralateral hyperhidrosis following an anterior thalamic infarction without the presence of a hypothalamic lesion. We speculated that the thalamus could share sudomotor fiber components in the crossed contralateral inhibitory sweating pathway.

Structural and functional brain changes beyond visual system in patients with advanced glaucoma.

In order to test the hypothesis that in primary open angle glaucoma (POAG), an important cause of irreversible blindness, a spreading of neurodegeneration occurs through the brain, we performed multimodal MRI and subsequent whole-brain explorative voxelwise analyses in 13 advanced POAG patients and 12 age-matched normal controls (NC). Altered integrity (decreased fractional anisotropy or increased diffusivities) of white matter (WM) tracts was found not only along the visual pathway of POAG but also in nonvisual WM tracts (superior longitudinal fascicle, anterior thalamic radiation, corticospinal tract, middle cerebellar peduncle). POAG patients also showed brain atrophy in both visual cortex and other distant grey matter (GM) regions (frontoparietal cortex, hippocampi and cerebellar cortex), decreased functional connectivity (FC) in visual, working memory and dorsal attention networks and increased FC in visual and executive networks. In POAG, abnormalities in structure and FC within and outside visual system correlated with visual field parameters in the poorer performing eyes, thus emphasizing their clinical relevance. Altogether, this represents evidence that a vision disorder such as POAG can be considered a widespread neurodegenerative condition.

Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex, but enrichment rescues CA1 spines only.

Injury to the anterior thalamic nuclei (ATN) may affect both hippocampus and retrosplenial cortex thus explaining some parallels between diencephalic and medial temporal lobe amnesias. We found that standard-housed rats with ATN lesions, compared with standard-housed controls, showed reduced spine density in hippocampal CA1 neurons (basal dendrites, -11.2%; apical dendrites, -9.6%) and in retrospenial granular b cortex (Rgb) neurons (apical dendrites, -20.1%) together with spatial memory deficits on cross maze and radial-arm maze tasks. Additional rats with ATN lesions were also shown to display a severe deficit on spatial working memory in the cross-maze, but subsequent enriched housing ameliorated their performance on both this task and the radial-arm maze. These enriched rats with ATN lesions also showed recovery of both basal and apical CA1 spine density to levels comparable to that of the standard-housed controls, but no recovery of Rgb spine density. Inspection of spine types in the CA1 neurons showed that ATN lesions reduced the density of thin spines and mushroom spines, but not stubby spines; while enrichment promoted recovery of thin spines. Comparison with enriched rats that received pseudo-training, which provided comparable task-related experience, but no explicit spatial memory training, suggested that basal CA1 spine density in particular was associated with spatial learning and memory performance. Distal pathology in terms of reduced integrity of hippocampal and retrosplenial microstructure provides clear support for the influence of the ATN lesions on the extended hippocampal system. The reversal by postoperative enrichment of this deficit in the hippocampus but not the retrosplenial cortex may indicate region-specific mechanisms of recovery after ATN injury.